A. The Need to Manufacture MR Contrast Agents Exhibiting the Lowest Possible Rates of Adverse Reactions
The efficacy of superparamagnetic colloids as parenteral, MR contrast agents (U.S. Pat. No. 4,827,945; U.S. Pat. 4,770,183; Stark et al. Radiology 168:297-301 (1988); Hemmingsson et al. Acta Radiologica 28:703-705 (1987)) has generated the need to produce these materials in sterile form, with the lowest possible incidence of (or degree of) adverse reactions resulting from their injection. (The foregoing two United States patents are hereby incorporated herein by reference.) An adverse reaction is an undesirable physiological response, sensation or symptom that occurs after the injection of a contrast agent. Examples of adverse reactions include blood pressure alterations, hives, vomiting and headache (see Dean, P.B. and Paajanen, H. "Undesirable Consequence of Intravascular Contrast Media Administration" in Contrast Media: Bioloqical Effects and Clinical Aoolication. (Parvez, Z., Moncada, R. and Sovak, M. eds., (CRC Press, Boca Raton, FL) vol. I, pp. 69-75). The commercial value of superparamagnetic colloids as parenteral MR contrast agents depends not only on the efficacy of a particular active ingredient, and the lack of acute toxicity, but on the ability to manufacture that ingredient in a manner consistent with stringent sterility requirements on the one hand, while producing the lowest possible incidence of (or degree of) adverse reactions on the other hand.
The need to minimize adverse reactions for MR contrast agents involves two considerations. First, governmental agencies regulating the sale of pharmaceuticals must be convinced that the incidence (or degree of) of adverse reactions is sufficiently low to permit the manufacturer to sell the agent. Second, within the competitive commercial marketplace, the relative incidence of adverse reactions exhibited by various agents, each approved for sale and each having a similar medical use, can determine the market share (or price obtained) for each agent. Each of these factors is discussed further below.
The need for contrast media to exhibit a very low incidence of adverse reactions in order to be approved by government agencies regulating their sale reflects the fact that such agents may be administered to individuals suspected of, but in fact free of, disease. Therapeutic agents are generally given to a population exhibiting some pathological condition, and those individuals benefit from the administration of the agent. With therapeutic agents a larger degree of adverse reactions may be to tolerated. For example, many of the agents used in cancer chemotherapy cause a number of adverse reactions or side effects.
Even when contrast media are sufficiently safe for regulatory agencies to approve their use in humans, the relative incidence of adverse reactions obtained with competing products can affect the market share, or price obtained for specific agents. For example, so-called nonionic angiographic contrast media have been developed and marketed as superior to ionic contrast media because the former, though more expensive, are believed to exhibit lower rates of adverse reactions (McClennan, B.L. Radiology 62:1-8 (1987)). In the marketplace of diagnostic contrast media, the ability to minimize even low rates of adverse reactions (e.g. reactions in 0.01-10.0% of those persons injected), can strengthen the commercial position of one product relative to another.